Autophagy refers to the lysosomal degradation of damaged or superfluous organelles and protein to recycle cellular constituents and nutrients for maintaining cellular homeostasis. Autophagy starts with the formation and expansion of an isolated membrane, which can elongate and form a double-membrane vesicle called the autophagosome. All engulfed cytoplasmic materials are then sequestered inside the autophagosome, which subsequently fuse with the lysosome for degradation [1]. While autophagy is constitutively active at low basal level [2], it is also responsible for regulating normal neuronal homeostasis [3]. It has been reported that defects in autophagy regulation such as SQSTM1(p62) mutations [4], autophagy related gene (Atg) 9 mislocation [5] and mutant huntingtin-mediated aggregation of beclin-1 or mTOR[6,7], are associated with neurodegenerative disorders including Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease and Huntington's disease, respectively. In mouse models with defective autophagy function, neurodegeneration and protein inclusions accumulation were reported [8]. This suggests the essential role of autophagy in maintaining healthy neurons and modulating neurodegenerative disorders through effective protein quality control. In fact, regular protein quality control on neurons is important because mutant proteins and damaged organelles cannot be reduced through cell division in neurons, and therefore, these malfunctioned structures must be identified and cleared through autophagic degradation before they accumulate and lead to neurotoxicity [3,9].
With the protective effects of lowering the level of toxic protein aggregates, autophagy has recently become an attractive therapeutic target for neurodegenerative disorders. Huntington disease (HD), a neurodegenerative disease characterized by progressive motor dysfunction and dementia [10], is caused by a larger than 35 CAG trinucleotide repeat expansion which results in a long mutant polyglutamine tract in the huntingtin protein [11]. These polyglutamine expansions are highly associated with cytotoxicity and aggregates formation [12,13]. Therefore, the identification of compounds that enhance autophagy in Huntington's disease is highly desirable. Recently, a United States Food and Drug Administration-approved drug, rilmenidine, is reported for its ability to induce autophagy and attenuate the toxicity of mutant huntingtin in a mouse model of Huntington's disease [10]. Another neuroprotective dietary flavonoid, fisetin, can induce autophagic cell death through mTOR pathway [14,15]. Furthermore, rapamycin, an inducer of mammalian target of rapamycin (mTOR)-dependent autophagy, is effective in increasing the autophagic clearance of mutant huntingtin fragments in vivo [7,16,17]. However, while mTOR inhibition can affect protein synthesis and cell proliferation [1,18], fisetin has the disadvantage of high effective concentration, low lipophilicity and poor bioavailability [14]. Therefore, alternate chemicals that can enhance the autophagic clearance of mutant aggregate-prone proteins with fewer side effects are desirable.